DOT1L explained

DOT1-like (Disruptor of telomeric silencing 1-like), histone H3K79 methyltransferase (S. cerevisiae), also known as DOT1L, is a protein found in humans, as well as other eukaryotes.^[1]

DOT1L has been reported to play an important role in the processes of mixed-lineage leukemia (MLL)-rearranged leukemias.^[2] DOT1L also plays a role in spermatogenesis, where it acts as a transcriptional activator for genes responsible for the histone-to-protamine transition.^[3]

Small molecule inhibitors of Dot1L catalytic activity have been developed.^{[4] [5]}

All three forms of H3K79 methylation (H3K79me1; H3K79me2; H3K79me3) are catalyzed by DOT1 in yeast or DOT1L in mammals. H3K79 methylation participates in the DNA damage response and has multiple roles in nucleotide excision repair and sister chromatid recombinational repair.^[6]

Further reading

• Nagase T, Nakayama M, Nakajima D, Kikuno R, Ohara O . Prediction of the coding sequences of unidentified human genes. XX. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro . DNA Research . 8 . 2 . 85–95 . April 2001 . 11347906 . 10.1093/dnares/8.2.85 . free .
• Feng Q, Wang H, Ng HH, Erdjument-Bromage H, Tempst P, Struhl K, Zhang Y . Methylation of H3-lysine 79 is mediated by a new family of HMTases without a SET domain . Current Biology . 12 . 12 . 1052–8 . June 2002 . 12123582 . 10.1016/S0960-9822(02)00901-6 . 2002CBio...12.1052F . 17263035 .
• Min J, Feng Q, Li Z, Zhang Y, Xu RM . Structure of the catalytic domain of human DOT1L, a non-SET domain nucleosomal histone methyltransferase . Cell . 112 . 5 . 711–23 . March 2003 . 12628190 . 10.1016/S0092-8674(03)00114-4 . 17822742 . free .
• Jikuya H, Takano J, Kikuno R, Hirosawa M, Nagase T, Nomura N, Ohara O . Characterization of long cDNA clones from human adult spleen. II. The complete sequences of 81 cDNA clones . DNA Research . 10 . 1 . 49–57 . February 2003 . 12693554 . 10.1093/dnares/10.1.49 . free .
• Okada Y, Feng Q, Lin Y, Jiang Q, Li Y, Coffield VM, Su L, Xu G, Zhang Y . hDOT1L links histone methylation to leukemogenesis . Cell . 121 . 2 . 167–78 . April 2005 . 15851025 . 10.1016/j.cell.2005.02.020 . 15638573 . free .
• Sistayanarain A, Tsuneyama K, Zheng H, Takahashi H, Nomoto K, Cheng C, Murai Y, Tanaka A, Takano Y . Expression of Aurora-B kinase and phosphorylated histone H3 in hepatocellular carcinoma . Anticancer Research . 26 . 5A . 3585–93 . 2006 . 17094487 .

Notes and References

1. Web site: Entrez Gene: DOT1L DOT1-like, histone H3 methyltransferase (S. cerevisiae).
2. Slany RK . The molecular mechanics of mixed lineage leukemia . Oncogene . 35 . 40 . 5215–5223 . October 2016 . 26923329 . 10.1038/onc.2016.30 . 34116587 . free .
3. Malla AB, Rainsford SR, Smith ZD, Lesch BJ . DOT1L promotes spermatid differentiation by regulating expression of genes required for histone-to-protamine replacement . Development . 150 . 9 . May 2023 . 37082969 . 10259660 . 10.1242/dev.201497 .
4. Yao Y, Chen P, Diao J, Cheng G, Deng L, Anglin JL, Prasad BV, Song Y . Selective inhibitors of histone methyltransferase DOT1L: design, synthesis, and crystallographic studies . Journal of the American Chemical Society . 133 . 42 . 16746–9 . 2011 . 21936531 . 3492951 . 10.1021/ja206312b .
5. Chen S, Li L, Chen Y, Hu J, Liu J, Liu YC, Liu R, Zhang Y, Meng F, Zhu K, Lu J, Zheng M, Chen K, Zhang J, Jiang H, Yao Z, Luo C . Identification of Novel Disruptor of Telomeric Silencing 1-like (DOT1L) Inhibitors through Structure-Based Virtual Screening and Biological Assays . Journal of Chemical Information and Modeling . 56 . 3 . 527–34 . 2016 . 26914852 . 10.1021/acs.jcim.5b00738 .
6. Chen Y, Zhu WG . Biological function and regulation of histone and non-histone lysine methylation in response to DNA damage . Acta Biochim. Biophys. Sin. (Shanghai) . 48 . 7 . 603–16 . July 2016 . 27217472 . 10.1093/abbs/gmw050 . free .